Adult mesenchymal stem cells (MSCs) have been found in a variety of adult tissues. Having been first identified in the bone marrow, MSCs are now accepted to reside in other tissues of mesodermal origin: adipose tissue, placenta, umbilical cord, dental pulp, synovium. Despite ample efforts, no exclusive individual surface markers have been identified for MSCs. MSCs are defined according to the three criteria of the International Society for Cellular Therapy: a) Adhesion to plastic: MSCs can be isolated by adhesion to plastic and expanded in vitro in serum containing media with no additional requirements for growth factors or cytokines; b) Expression of a specific combination of surface markers: MSCs are negative for hematopoietic and endothelial markers such as CD11b, CD14, CD31, CD34 and CD45, and positive for a variety of other markers, including HLA class I, CD73, CD90 and CD105; c) Differentiation potential: MSCs can be identified in vitro by their ability to differentiate into mesenchymal-type cells (e.g. trilineage differentiation into adipocytes, osteoblasts and chondrocytes). MSCs are at least tripotent at early stages which may be reduced to e.g. bipotent or unipotent cells in the course of in vitro expansion processes. Although sharing these main characteristics, differences between MSCs from different sources can be found. Accordingly, the secretome differs between cell types, and bone marrow-derived MSCs (BM-MSCs) and adipose-derived MSCs (ASCs) show specific RNA and protein expression profiles.
MSCs are considered a promising tool for cell therapy in regenerative medicine, or for treating other diseases such as ischemic, inflammatory and immune diseases. Although in situ differentiation was initially thought to be the basis of their therapeutic properties (i.e. structural tissue regeneration), it is now believed that their immunomodulatory capacity and paracrine effects through trophic factors with anti-fibrotic, anti-apoptotic or pro-angiogenic properties are the more likely mechanisms of their therapeutic effect.
MSCs show immunomodulation properties and regulate the function (proliferation, activation and effector function) of a broad variety of immune cells including B lymphocytes, T lymphocytes, NK cells, monocyte-derived dendritic cells and neutrophils. The specific molecular and cellular mechanisms involved in the immunoregulatory activity of MSCs are still under investigation but rely on both cell contact-dependent mechanisms (i.e. through Jagged1-Notch1 interaction) and paracrine effects through the release of soluble factors including hepatocyte growth factor (HGF), prostaglandin-E2 (PGE2), transforming growth factor (TGF)-beta 1, indoleamine 2,3-dioxygenase (IDO), nitric oxide (NO), interleukin (IL)-10, IL-6, heme oxygenase-1 (HO-1) or HLA-G5. Furthermore, MSCs may also modulate immune responses through the generation of Regulatory T cells (Tregs). These cells are defined by the expression of CD4, CD25 and the transcription factor Forkhead box p3 (Foxp3), and play a central role in protecting from autoimmunity through their immunosuppressive capacity.
In addition to this immunomodulatory capacity, an additional potential advantage of the clinical use of MSC is that the immunogenicity of MSC is considered to be low. This is due to the fact that the expression of HLA class I is low, and HLA class II and the classic co-stimulatory molecules CD40, CD80 and CD86 are not detectable.
One of the first reported (1995) clinical trials involving MSC was the bone marrow derived stromal progenitor cell therapy in the treatment of patients having hematologic malignancies. Since then numerous clinical trials have been carried out and the first marketing authorizations have been granted for MSC therapies. Currently there are several hundred trials reported involving MSC, for the treatment of indications including bone disorders (e.g. bone cysts, cleft palate, osteonecrosis, spinal fusion), cartilage disorders (e.g. articular cartilage repair and meniscus repair), hematologic disorders (e.g. anaemia, myelodysplastic syndrome), metabolic diseases (e.g. Type I & II diabetes), liver diseases (e.g. cirrhosis & failure), cardiovascular diseases (e.g. AMI), gastrointestinal disorders (e.g. IBD and anal fistula), autoimmune disorders (e.g. rheumatoid arthritis and Crohn's disease), pulmonary diseases (e.g. COPD and IPF), neurological diseases (e.g. MS, stroke and disc degeneration), renal diseases (e.g. kidney failure and renal transplant), urogenital disorders (e.g. urinary incontinence & erectile dysfunction) and ophthalmological diseases (e.g. retinitis pigmentosa).
While such on-going investigations illustrate the potential of MSCs in treating a wide variety of diseases and disorders the use of biomarkers for the prediction of treatment response may potentially aid in the development and use of such therapies.